The chemical name of the active substance ifosfamide is 3-(2-chloroethyl)-2-(chloroethylamino)-tetrahydro-2H-1, 3,2-oxazaphosphorin-2-oxide ##STR1##
In common with cyclophosphamide, ifosfamide belongs to the chemical group of oxazaphosphorins and is used therapeutically for the treatment of tumor diseases.
The chemical name of the uroprotector mesna is sodium2-mercaptoethanesulphonate. EQU Na.sup.+ [HS--CH.sub.2 --CH.sub.2 --SO.sub.3 ]-
Mesna protects, for example, the urinary tract in the treatment of tumor diseases with ifosfamide, this uroprotective action of mesna being present in particular when it is administered simultaneously and synchronously together with ifosfamide.
Ifosfamide is a white crystalline powder having a melting point of 48.degree. C. to 51.degree. C. and pronounced hygroscopic properties. Ifosfamide begins to sinter below its melting point and must therefore be stored at temperatures that are as low as possible (room temperature and below). Contact with humidity is also to be avoided as much as possible.
Ifosfamide dissolves in water to the extent of about 10 percent by weight, but is only stable to a limited extent in aqueous solution (a maximum of 3 to 4 hours at 20.degree. C. to 22.degree. C. or 36 hours at 4.degree. to 6.degree. C.
Ifosfamide is only administered parenterally. The injection bottles contain 200 to 5000 m of ifosfamide in the form of a sterile crystallizate which is dissolved in water for injection purposes before administration so that a 4% concentration is not exceeded. This solution is suitable for intravenous injection. For intravenous short infusion the ifosfamide solution is dissolved in 500 ml of Ringer's solution or a similar infusion liquid. The duration of the infusion is ca. 30 minutes, possibly 1 to 2 hours. In the case of the 24-hour infusion, the ifosfamide solution is, for example, dissolved in a total of 3 liters of 5% dextrose-common salt solution.
There are numerous problems associated with the preparation and processing of ifosfamide. During the preparation of sterile, crystallized ifosfamide a product is obtained having an unstable physical nature. In particular, the fluctuating flow properties greatly impair accuracy of dosage during filling.
The processing of ifosfamide is further impeded by its hygroscopic nature and the low melting point. If stored for a longer period of time the sterile crystallizate sinters and the speed of dissolution falls. As ifosfamide begins to sinter, the clarity and pH value of the solution also decrease with simultaneous yellow discoloration and therapeutic use is then generally no longer possible.
Mesna is also a substance that is only stable and storable under special conditions.
It has not been possible, hitherto, to combine ifosfamide and mesna, even though this would represent a great advantage with regard to storage and practical handling.